Dokument: Einfluss von Hypoxie auf die antimikrobiellen und immunregulatorischen Wirkungen der Indolamin 2,3-Dioxygenase
| Titel: | Einfluss von Hypoxie auf die antimikrobiellen und immunregulatorischen Wirkungen der Indolamin 2,3-Dioxygenase | |||||||
| Weiterer Titel: | Regulation of IDO activity by oxygen supply: inhibitory effects on antimicrobial and immunoregulatory functions | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=42863 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20170717-081208-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Ebel, Sebastian [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Däubener, Walter [Gutachter] Prof. Dr. Drexler, Ingo [Gutachter] | |||||||
| Stichwörter: | Hypoxie IDO Indolamin 2,3-Dioxygenase Trypophan | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Tryptophan ist sowohl für den Menschen, als auch für viele Mikroorganismen eine essenzielle Aminosäure. Daher hat die Tryptophankonzentration im Gewebe auch Auswirkungen auf das Wachstum von Mikroorganismen. Die vorgelegte Arbeit beschäftigt sich mit in vitro- Modellen für bakterielle, parasitäre und virale Infektionen. Hierbei liegt ein besonderer Schwerpunkt auf den durch das Enzym Indolamin 2,3-Dioxygenase (IDO) vermittelten antimikrobiellen und immunregulatorischen Effekten. Bei der IDO handelt es sich um eine Dioxygenase, das bedeutet, dass sie die Spaltung von Tryptophan nur unter Verwendung von Sauerstoff katalysiert.
In vivo finden sich in unterschiedlichen Gewebetypen unterschiedliche Sauerstoff- konzentrationen die einen Einfluss auf die IDO Aktivität besitzen könnten. In der vorliegenden Arbeit wurde daher untersucht, ob physiologisch oder pathophysiologisch normale Sauerstoffkonzentrationen von 1 - 10% O2 die IDO Aktivität beeinflussen. Es konnte gezeigt werden, dass die Enzymaktivität der IDO bei pathophysiologisch relevanten, niedrigen Sauerstoffkonzentrationen deutlich reduziert ist. Folgerichtig war eine IDO-vermittelte, auf Tryptophanmangel beruhende Hemmung des bakteriellen Wachstums unter hypoxischen Bedingungen nicht mehr nachzuweisen. Ähnliche Effekte konnten auch in Infektionssystemen mit Viren und Parasiten beobachtet werden. Auch die immunregulatorischen Funktionen der IDO bei der Aktivierung von T-Zellen konnten durch Hypoxie vergleichbar blockiert werden. Damit konnte im Rahmen dieser Arbeit gezeigt werden, dass die Effektivität der IDO vermittelten Tryptophandegradation in humanen Vorhautfibroblasten und in humanen Glioblastomzellen essenziell von einer ausreichenden Versorgung mit Sauerstoff abhängt und dass die O2 Konzentration somit die Ausprägung antimikrobieller und immunregulatorischer Effektorleistung beeinflusst.Tryptophan is an essential amino acid for human beings as well as for some microorganisms. In human cells the interferon-γ (IFN-γ) inducible enzyme indoleamine 2,3-dioxygenase (IDO) reduces local tryptophan levels and is therefore able to mediate broad-spectrum effector functions: IDO activity restricts the growth of various clinically relevant pathogens such as bacteria, parasites and viruses. On the other hand, it has been observed that IDO has immunoregulatory functions as it efficiently controls the activation and survival of T-cells. Although these important effects have been analysed in much detail, they have been observed in vitro using cells cultured in the presence of 20% O2 (normoxia). Such high oxygen concentrations are not present in vivo especially within infected and inflamed tissues. We therefore analysed IDO-mediated effects under lower oxygen concentrations in vitro and observed that the function of IDO is substantially impaired in tumour cells as well as in native cells. Hypoxia led to reduced IDO expression and as a result to reduced production of kynurenine, the downstream product of tryptophan degradation. Consequently, effector functions of IDO were abrogated under hypoxic conditions: in different human cell lines such as tumour cells (glioblastoma, HeLa) but also in native cells (human foreskin fibroblasts; HFF) IDO lost the capacity to inhibit the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) or viruses (herpes simplex virus type 1). Additionally, IDO could no longer efficiently control the proliferation of T-cells that have been co-cultured with IDO expressing HFF cells in vitro. In conclusion, the potent antimicrobial as well as immunoregulatory functions of IDO were substantially impaired under hypoxic conditions that pathophysiologically occurs in vivo. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Medizinische Mikrobiologie | |||||||
| Dokument erstellt am: | 17.07.2017 | |||||||
| Dateien geändert am: | 17.07.2017 | |||||||
| Promotionsantrag am: | 15.11.2016 | |||||||
| Datum der Promotion: | 13.07.2017 |
